The specific aims of this proposal will be to propagate and clone T lymphocytes with specific function in order to elucidate the cellular mechanisms inherent in the epitope restricted unresponsiveness exhibited by certain strains of mice to well defined protein antigens such as cytochrome c. Our laboratory has made the observations that the unresponsive phenotype exhibited to beef cytochrome c by mice of the A.TL haplotype can be dissected into the capacity to respond to determinant(s) located on one peptide of the cytochrome c molecule but only when that peptide is presented away from the context of yet another peptide residue. The thesis to be tested is whether it is possible to demonstrate that, within the context of the A.TL haplotype, one set of determinants located in one part of beef cytochrome c induces suppressor T lymphocytes whose activity is dominant over T helper lymphocytes induced by determinants located in another part of the molecule. Mapping specific amino acid residues involved in the dominant suppressor effect will be attempted using specie variants of cytochrome c, peptide fragments and hybrid molecules which can be reconstituted from the appropriate peptides of different species of cytochrome c. In order to study the cellular interplay operational in such systems, clonally derived lines of T cells with specific functional capacity will be obtained according to protocols generated by our laboratory, and those of other investigators. Such cells will be used not only to define specific interactions occurring in the response to protein antigens but also to gain insights into the means by which different T cell subsets regulate each other and either affect or are affected by other cellular components of the immune system, namely macrophages and B lymphocytes. The issues presently considered are critical to an understanding of antigen recognition and regulation of the immune system. Their resolution should provide better insight with which to modulate immunity in a specific manner, a goal which provides the practical driving force to fuel basic studies in immunobiology.